CN102232184A - Automatic isothermal titration microcalorimeter apparatus and method of use - Google Patents

Automatic isothermal titration microcalorimeter apparatus and method of use Download PDF

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Publication number
CN102232184A
CN102232184A CN2009801490819A CN200980149081A CN102232184A CN 102232184 A CN102232184 A CN 102232184A CN 2009801490819 A CN2009801490819 A CN 2009801490819A CN 200980149081 A CN200980149081 A CN 200980149081A CN 102232184 A CN102232184 A CN 102232184A
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syringe
titrant
pond
sample
cleaning
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CN102232184B (en
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M·布罗加
P·E·普里塞
S·史密斯
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Malvern Panalytical Inc
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Amersham Biosciences Corp
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N25/00—Investigating or analyzing materials by the use of thermal means
    • G01N25/20—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity
    • G01N25/48—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity on solution, sorption, or a chemical reaction not involving combustion or catalytic oxidation
    • G01N25/4873—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity on solution, sorption, or a chemical reaction not involving combustion or catalytic oxidation for a flowing, e.g. gas sample
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02—Burettes; Pipettes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/52—Containers specially adapted for storing or dispensing a reagent
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/02—Devices for withdrawing samples
    • G01N1/10—Devices for withdrawing samples in the liquid or fluent state
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N25/00—Investigating or analyzing materials by the use of thermal means
    • G01N25/20—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity
    • G01N25/48—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity on solution, sorption, or a chemical reaction not involving combustion or catalytic oxidation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N25/00—Investigating or analyzing materials by the use of thermal means
    • G01N25/20—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity
    • G01N25/48—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity on solution, sorption, or a chemical reaction not involving combustion or catalytic oxidation
    • G01N25/4846—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity on solution, sorption, or a chemical reaction not involving combustion or catalytic oxidation for a motionless, e.g. solid sample
    • G01N25/4866—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity on solution, sorption, or a chemical reaction not involving combustion or catalytic oxidation for a motionless, e.g. solid sample by using a differential method
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/00584—Control arrangements for automatic analysers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/00584—Control arrangements for automatic analysers
    • G01N35/0092—Scheduling
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1002—Reagent dispensers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00—Supporting devices; Holding devices
    • B01L9/54—Supports specially adapted for pipettes and burettes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01K—MEASURING TEMPERATURE; MEASURING QUANTITY OF HEAT; THERMALLY-SENSITIVE ELEMENTS NOT OTHERWISE PROVIDED FOR
    • G01K17/00—Measuring quantity of heat
    • G01K17/006—Microcalorimeters, e.g. using silicon microstructures
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/02—Devices for withdrawing samples
    • G01N1/10—Devices for withdrawing samples in the liquid or fluent state
    • G01N1/14—Suction devices, e.g. pumps; Ejector devices
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
    • G01N35/04—Details of the conveyor system
    • G01N2035/0474—Details of actuating means for conveyors or pipettes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N25/00—Investigating or analyzing materials by the use of thermal means
    • G01N25/20—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N25/00—Investigating or analyzing materials by the use of thermal means
    • G01N25/20—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity
    • G01N25/48—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity on solution, sorption, or a chemical reaction not involving combustion or catalytic oxidation
    • G01N25/4806—Details not adapted to a particular type of sample
    • G01N25/4813—Details not adapted to a particular type of sample concerning the measuring means

Abstract

Automated isothermal titration micro calorimetry (ITC) system comprises a micro calorimeter with a sample cell and a reference cell, wherein the sample cell is accessible via a sample cell stem and the reference cell is accessible via a reference cell stem. The system further comprises an automatic pipette assembly comprising a syringe with a titration needle arranged to be inserted into the sample cell for supplying titrant, the pipette assembly comprises an activator for driving a plunger in the syringe, a pipette translation unit supporting the pipette assembly and being arranged to place pipette in position for titration, washing and filling operations, a wash station for the titrant needle, and a cell preparation unit arranged to perform operations for replacing the sample liquid in the sample cell when the pipette is placed in another position than the position for titration.

Description

Automatic isothermal titration microcalorimeter device and using method
Background of invention
The present invention relates generally to microcalorimeter, and more particularly, relates to and improve the microcalorimeter feature of the performance of the isothermal titration hot system of trace (ITC system) especially automatically.
Microcalorimeter is widely used for biological chemistry, pharmacology, cell biology and other field.The direct method that calorimetry provides a kind of macroscopic property that is used to measure biomacromolecule to change.The normally two ponds of microcalorimeter instrument, wherein the character of the dilute solution of the substances in the damping fluid in the sample cell is compared with the damping fluid of equal quantities in the reference pond continuously.Difference is owing to there being substances in the sample cell between two pond character of measured this (for example temperature or heat flux).
One type microcalorimeter is the isothermal titration calorimeter.Isothermal titration calorimeter (ITC) is a kind of differential attachment, though the liquid in the sample cell by continuous stirring, it is operated under fixing temperature and pressure.The most general application of titration calorimetry is to characterize the thermodynamics of interaction of molecules.In this application, the dilute solution of substances (for example protein) is placed in the sample cell, and at different time a spot of second dilute solution that comprises ligand (this ligand binding is on substances) is injected sample cell.The heat that this apparatus measures is emitted or absorbed owing to new ligand binding to the substances of introducing.For special pairing between substances and the ligand, can determine for example variation of gibbs energy, association constant, enthalpy and entropy and the such character of stoichiometry of binding from the result of repeatedly injection test.
Though the ITC that utilizes provides reliable binding data result at present, but its extensive utilization at the commitment of drug research is subjected to the restriction of some factors: the protein of the fixed needed high relatively quantity of execute key translocation (for example about 0.1 milligram (mg) is to the protein of about 1.0mg), measure the limited treatment capacity that the needed time causes owing to carrying out, and the complicacy of utilizing conventional I TC.
At present, utilize the ITC collection binding data of prior art to need a large amount of preparation of professional and skill.For example, utilize the ITC of prior art, at first fill with reference to pond and sample cell with reference substance and sample material respectively via corresponding pond post.Subsequently, with the buret of titrant filling ITC, this is a kind of meticulous operation, because accurately fill the syringe in the transfer pipet and make that it is very important not having air entrapment inside.Via Chi Zhu the pin of buret manually is placed in the sample cell then, and can begins the ITC test.It is working procedures such as computing machine with the control of the control module that is used to carry out test that the ITC measuring process is subjected to form.Corresponding to the program that is used to test is that stirring motor makes the speed rotation with appointment of syringe, pin and paddle, thereby allows the suitable mixing of reagent.Corresponding to the program that is used to test is (for example when reaching uniform temperature and/or reaching balance), and the plunger in the syringe is energized, thereby titrant is injected sample solution.Depend on program setting, this injection is (length by length) or carry out continuously discontinuously.The exothermic/endothermic that calorimeter is measured continuously and record is associated with the interaction of reagent with respect to the time.Can analyze the result according to the algorithm of setting up.
As intelligible like that by the process of reading above-mentioned prior art, utilize the ITC of prior art, greatly depend on operator's skill and experience with the quality of the binding measurement of the ITC execution of these prior aries, and relate to quite a large amount of setup times.
There has been at least a automatic ITC system for a period of time on the market, MicroCal AutoITC, it is based on commercially available microcalorimeter and linear machine robot system and is set to carry out fluidic system that automatic sample handles.
Summary of the present invention
The objective of the invention is to, provide a kind of new automatic isothermal titration micro-hot system (ITC system), this ITC system has overcome one or more shortcomings of prior art.This realizes by the ITC system defined in the independent claims.
An advantage of this ITC system is that compare with prior art, each burette test needs less time.This is owing to for example reduced pool volume, and the cleaning of transfer pipet assembly and sample cell and heavily to fill be executed in parallel substantially.Therefore, compare with prior art system, system throughput is significantly higher, and this makes may assess a large amount of samples to screen the test of type.
Another advantage is that the ITC system can be provided with and be used for carrying out a large amount of unattended burette tests.
Define embodiments of the invention in the dependent claims.
The accompanying drawing summary
Fig. 1 has shown a schematic example of the manual ITC system of prior art in the cross section, this ITC system comprises the aupette assembly.
Fig. 2 has shown the synoptic diagram of an embodiment of automatic ITC system.
Fig. 3 a and Fig. 3 b have shown the synoptic diagram of other embodiment of automatic ITC system.
Fig. 4 a and Fig. 4 b have shown the synoptic diagram of two embodiment of the injecting type fluidic system that is used for automatic ITC system.
Fig. 5 a has shown synoptic diagram according to the effect of the syringe fill port connector unit of an embodiment to Fig. 5 c.
Fig. 6 has shown the synoptic diagram of preparing fluidic system according to the pond of an embodiment.
Fig. 7 has schematically shown the different operating state of the ITC system of Fig. 2.
Fig. 8 a shows the different operating state of the ITC system of Fig. 2 in greater detail to Fig. 8 d.
Detailed description of the present invention
Showed the manual ITC system 10 of disclosed type among Fig. 1 in PCT application PCT/US2008/081961, it is incorporated by reference herein.According to an embodiment, this manual ITC system 10 is used as microcalorimeter in this automatic ITC system, but in other embodiments, microcalorimeter is other type, as will discussing in more detail below.In disclosed manual ITC system 10, to compare with the ITC of prior art, it is about 1/7th that the pond compartment volume is reduced to, desensitization not simultaneously, and have the response time significantly faster.Such ITC system allows to utilize and is reduced to about 1/10th protein example execution test, and carries out test under the situation of per hour only carrying out about 2 to 4 titration altogether.Test the cost that is associated except reducing with carrying out ITC, littler pool volume has also been expanded the quantity that ITC uses.For example, indicated the scope of the binding affinity that can be measured by ITC by the parameter that is called as " c value ", it equals binding affinity (K a) and macromolecular total concentration (M Total) product (c=[M Total] Ka).For accurate affinity was measured, the c value must be between 1 and 1,000.If use the protein of same amount, pool volume is reduced to the 1/10 similar increase that can cause c value, thereby and causes the ability of measurement low binding.This ability is a particular importance at the commitment (wherein the binding affinity is weak) of drug discovery, especially combines with fully automatic instrument.
Fig. 1 has schematically shown an embodiment of manual ITC system 10, and it can be according to the present invention and robotization.ITC system 10 comprises microcalorimeter 20 and aupette assembly 30.Microcalorimeter 20 comprises that with reference to pond 40 and sample cell 50, it is designing basic identically aspect thermal capacity and the volume.Pond 40 and 50 materials by suitable chemically inert and heat conduction (for example gold, platinum, tantalum, haas troy alloy or the like) constitute.Pond 40 and 50 can be any basically suitable shape, is identical shape but need it, and can be arranged to the layout of symmetry fully, and can realize that titrant mixes with the effective of sample.In disclosed embodiment, pond 40 and 50 cross section are rectangles, and the cross section on the transverse horizontal direction can be circular, cause having the pond of the coin shapes of circular lining face.
Minimum for any external heat influence is reduced to, all to be sealed with reference to pond 40 and sample cell 50 by first heat shield 60, first heat shield 60 is sealed by second heat shield 70 again. Heat shield 60,70 can be made of any suitable Heat Conduction Material (for example silver, aluminium, copper or the like). Heat shield 60,70 also can be made of the sub-heat shield (not shown) that one or more heat link to each other, so that provide even more stable temperature conditions for calorimetric pond 40,50.
In order to control the temperature of heat shield 60,70, heat control device can be set, to control its temperature.In a kind of ITC system, described heat control device is mainly used in (that is heat shield 60,70) " isothermal " temperature of setting calorimeter before the beginning burette test.But as below will be more detailed disclosed, described heat control device also can be used to improve the heat-proof quality of calorimeter.According to an embodiment, heat control device is made of one or more heat pump units (for example based on thermoelectric heat pumping devices of peltier effect or the like).The heat control device of other type comprises the controlled liquid pool of constant temperature, mechanical heat pump, chemical heat or cooling system or the like.
In disclosed embodiment, first heat pump unit 80 is set to transferring heat energy between first heat shield 60 and second heat shield 70, second heat pump unit 90 is set to transferring heat energy between second heat shield 70 and heating radiator 100, and heating radiator 100 is in thermo-contact with environment temperature.Temperature controller 110 is set to control first heat pump unit 80 and second heat pump unit 90, thereby realizes required temperature conditions.Temperature controller 110 is monitored the temperature of first heat shields 60 and second heat shield respectively by the temperature sensor 120 and 130 that is associated.In addition, heat controller 110 is set to by pond heating arrangement 145 control pond temperature.Heat controller 110 is Be Controlled via the calorimeter user interface of operation on computing machine 150 or the like.Be used for to be connected computing machine 150 via for example prime amplifier 160 at ITC duration of test sensing sample cell 50 with reference to the calorimetric sensor 140 of the temperature difference between the pond 40.
Provide the path of arrival respectively with reference to pond post 170 and sample cell post 180, to be used to provide with reference to fluid and sample fluid, titration fluid, to the cleaning in pond or the like with reference to pond 40 and sample cell 50.In disclosed embodiment, Chi Zhu 170 and 180 all substantially vertically extends through heat shield and heating radiator, in order to providing about the contacting directly of pond 40 and 50, and supports its corresponding pond 40 and 50 in the cavity of pond post 170 and 180 each comfortable first heat shield 60.
Aupette assembly 30 comprises transfer pipet shell 190, syringe 200 and line driver 220, syringe 200 has and is set to be inserted in the sample cell 50 to be used for supplying with the titration pin 210 of titrant, and line driver 220 is used for the plunger 230 of injector-actuated 200.Titration pin 210 can rotate with respect to shell 190, and is provided with paddle 240, and paddle 240 is set to the sample fluid in the stirred sample pond 50, so that realize effective mixing of titrant and sample fluid.Aupette assembly 30 also comprises the stirring motor 250 that is used to drive 210 rotations of titration pin.
In the disclosed embodiments, stirring motor 250 is motors of a kind of direct driving in Fig. 1, and it has the hollow rotor with syringe 200 and the 210 concentric settings of titration pin.Syringe 200 is stirred motor 400 in the top and supports being used for rotation, and is supported by bearing 260 in the lower end.
In an alternative (not illustrating in the drawings), stirring motor 250 drives the rotation of titration pin by rotary actuator (for example belting, power wheel device or the like).In addition, stirring motor can be arranged with the transfer pipet assembly in 30 minutes, and was set to drive the rotation of titration pin by suitable gearing (for example magnetic coupling or the like).
Aupette assembly 30 is by the control of the controller of ITC system, for example stirring of sample and titration.
In disclosed embodiment, line driver 220 comprises step motor 270, it is set to drive threaded plunger 230, plunger 230 extends through the hole of hollow rotor coaxially and enters in the syringe 200, wherein, plunger 230 is rotatably connected to the transfer pipet top 280 of sealing against syringe 200 inwalls, to allow the vs that shifts definite volume from syringe 200.Line driver 220 can be any other type that can carry out controlled linear movement with enough precision.This design allows that the main part 190 of the relative transfer pipet assembly 30 of syringe rotates independently; Simultaneously, line driver 220 can drive threaded plunger 230.
According to Fig. 2 schematically disclosed embodiment in Fig. 8 d, a kind of automatic isothermal titration trace heat (ITC) system 300 is provided, it comprises:
● have sample cell 50 and with reference to the microcalorimeter 20 in pond 40, sample cell 50 can arrive via sample cell post 180, and can arrive via reference pond post 170 with reference to pond 40,
● aupette assembly 30, it comprises the syringe 200 of band titration pin 210, and titration pin 210 is set to be inserted in the sample cell 50 to be used to supply with titrant, and transfer pipet assembly 30 comprises line driver 220, and it is used for the plunger 230 of injector-actuated 200,
● transfer pipet shift unit 310, it supports transfer pipet assembly 30, and is set to transfer pipet to be placed on the position that is used for titration, cleaning and padding,
● be used for titration pin 210 cleaning station 320 and
● pond preparatory unit 330, it is set to when transfer pipet 30 is placed on the another location different with the position that is used for titration, and executable operations is to be used for changing the sample liquids of sample cell 50.
Microcalorimeter 20 can be to utilize the sample of enough small sizes to carry out any kind of ITC calorimetric measurement, the microcalorimeter 20 that for example schematically shows among Fig. 1.As top disclosed (Fig. 1), but in Fig. 8 d, do not show especially at Fig. 2, microcalorimeter generally includes sample cell 50 and with reference to pond 40, wherein, sample cell 50 can arrive via sample cell post 180, and can arrive via reference pond post 170 (shown in the circular open among Fig. 2) with reference to pond 40.Aupette assembly 30 can be top disclosed type, but it can have any suitable design, comprises the syringe 200 of band titration pin 210, and titration pin 210 is set to be inserted in the sample cell 50 to supply with titrant.With top similar, transfer pipet assembly 30 also can comprise line driver 220, and it is used for the plunger 230 of injector-actuated 200.Yet syringe 200 can be any kind that the titrant of clear and definite defined volume can be provided substantially.Titration pin 210 is rotatable, and can be provided with paddle 240, and it is used for the liquid in stirred sample pond 50 during titration.This stirring can realize as top the argumentation or with any other suitable manner.
Transfer pipet shift unit 310 can be any kind that transfer pipet can be placed on the correct position that is used for titration, cleaning and filling.Fig. 2 and Fig. 3 have schematically shown two kinds of dissimilar shift units, and wherein, Fig. 2 has shown rotation displacement unit 310, and Fig. 3 has shown linear displacement unit 310b.For titration pin 210 is placed in (insertion) correct position in sample cell 50 and/or in other position, transfer pipet shift unit 310 can make transfer pipet 30 move in vertical direction with respect to microcalorimeter 20.Transfer pipet shift unit 310 can mechanically be limited about its freedom of motion, thereby it can only be moved between mechanical preposition, perhaps it can be the conventional shift unit that is subjected to the robot type of limit movement by software parameter between described precalculated position, or its combination.For reason clearly, in Fig. 8 d, do not comprise such device that is used for vertical movement at Fig. 2.
Cleaning station 320 is arranged on suitable position, and wherein, the titration pin 210 of transfer pipet assembly 30 can be placed on the position that is used to clean.Cleaning station 320 can be any suitable type, and when transfer pipet assembly 30 was placed on the position that is used to clean, it can clean the part that immerses the titration pin 210 in the sample during titration at least.According to an embodiment, cleaning station 320 comprises the cleaning cavity 340 that is set to hold the titration pin.Cleaning station 320 is made by any suitable material, and it is an inertia with respect to employed reagent in ITC test and the clean cycle.According to an embodiment, cleaning station 320 comprises the Waste outlet port 350 that is positioned at place, cleaning cavity bottom, and it is connected refuse and removes on the unit 360.As following will be more detailed disclosed, Waste outlet port 350 is used to remove the cleaning solution during waste liquid and the transfer pipet clean cycle, and it preferably is arranged on the bottom of cleaning cavity 340, thereby the cleaning cavity is emptied completely.(among the figure not open) in one embodiment, transfer pipet shift unit 310 is subjected to limit movement in vertical direction, and cleaning 320 generations of station and be arranged to be movable to the position of aiming at pin 240, to be used to clean pin 240.
In Fig. 8 d, pond preparatory unit 330 is shown as the shift unit with transfer pipet shift unit 310 same types at Fig. 2, but is arranged to be positioned at least two positions relevant with cleaning and change sample liquids in the sample cell.By being provided for changing the pond preparatory unit 330 of the sample liquids in the sample cell 50, reduced total cycling time, and thereby improved the treatment capacity of ITC system 300 because can clean sample cell 50 also with new sample liquids filling sample pond 50 when filling transfer pipet 30 at cleaning transfer pipet 30 and with new titrant.
Fig. 2 schematically discloses according to an embodiment of the invention isothermal titration trace heat (ITC) system 300 automatically.As mentioned above like that the shift unit 310,330,370 among this embodiment is rotation type all, and all operations position all is that circumferential path along the rotation displacement unit is provided with.(not shown) in another embodiment, one or more rotation displacements unit is provided with extra linear displacement device, with the expansion perform region and improve flexible.
In Fig. 2, transfer pipet shift unit 310 comprises transfer pipet arm 380, and it is rotatably supported to be used for centering on axis A rotates, and supports transfer pipet assembly 30 at its other end.Transfer pipet arm 380 also is arranged to can vertically mobile transfer pipet, or since arm 380 can vertically be moved along axis A, or since arm 380 in a plane, rotate limited, but and transfer pipet 30 with respect to arm 380 vertical moving.Transfer pipet arm 380 is set to transfer pipet 30 is placed on correct position, to be used for:
● the titration pin is inserted into carry out in the sample cell 50 titration,
● the titration pin is inserted in the cleaning/filling station 320 of combination cleans and fill.
Cleaning/the fillings station 320 of combination can be the cleaning station of the type discussed above, wherein exports port 350 and locates in the bottom of cleaning cavity 340.Outlet port 350 is connected on the refuse fluidic system 360, and it will be discussed below in more detail.
Pond preparatory unit 330 comprises corresponding pond arm 390 again, it is rotatably supported to be used for the rotation around axis B, the pond intubate 400 of its support and connection on pond fluidic system 410 is to be used for distributing and to regain sample cell 50 and also may be at the liquid in the reference pond 40.Pond fluidic system 410 will be disclosed in more detail below.Pond arm 390 is configured such that pond intubate 400 moves to a plurality of positions, and for example the pond 40 and 50 of microcalorimeter, one or more sample source and sample are prepared station 420 or the like.In disclosed embodiment, comprise four different sample source positions, wherein the big volume sample reservoir 430a-430c of pipe-type bottles type is represented in three positions, for example be used for standard model liquid, and the 4th position is automatic sample position 440, for example be used for specific or sensitive sample liquids, wherein, pond intubate 400 is set to draw sample liquids from the certain well of sample tray 450 (for example minitype plate or the like).In disclosed embodiment, automatically sample position 440 is rest positions, pond intubate 400 can move to this position by pond arm 390, and be reduced in the certain well of sample tray 450, sample tray 450 can be moved, so that by pallet actuator (not shown) selected well is positioned automatic sample position 440.The pallet actuator can be any suitable type that can optionally the specific sample well of sample tray 450 be positioned at desired location, the rotary actuator of for example linear X-Y actuator or band rotating disc type pallet.Sample is prepared station 430 and is used in sample and prepares sample before being sent in pond 50 or 40, for example by making sample reach the temperature approaching with test temperature, or prepares sample by mixing degasification.
Disclosed ITC system 300 also comprises titrant delivery unit 370 among Fig. 2, and it is set to titrant is sent to cleaning/filling station 320 from the first titrant source (for example sample tray 450).In disclosed embodiment, delivery unit 370 comprises titrant transferring arm 460 (for example corresponding with pond transferring arm 380), and it is rotatably supported to be used for the rotation around axis C, and it is supporting the transmission intubate 470 that is connected on the injecting type fluidic system 480.Titrant transferring arm 460 is set to titrant intubate 470 is positioned in the automatic sample position 440, being used for drawing the titrant sample, and be set at the correct position that described titrant sample can be assigned in cleaning/filling station 320 from the titrant well of sample tray 450.With respect to the automatic sample position 440 of the top pond intubate of discussing, automatically sample position 440 and sample tray 450 can be independent position and pallets, but as disclosed among Fig. 2, pond intubate 470 and titrant intubate 400 can be positioned identical automatic sample position 440 (not being simultaneously), and the pallet actuator can be controlled to be for corresponding intubate suitable well is positioned automatic sample position 440.Injecting type fluidic system 480 also is connected on the fill port linkage unit 490, and fill port linkage unit 490 is arranged to optionally be connected on the fill port 500 of office, top of the syringe 200 in the transfer pipet assembly.In the time of on being connected to fill port 500, fill port linkage unit 490 provides fluid contact between syringe cavity and injecting type fluidic system 480, thus optionally pulling or promote liquid or gas passes syringe 200.
As previously mentioned, Fig. 3 a has shown the corresponding ITC system with the system of Fig. 2, still, and wherein, shift unit 310b, the 330b, the 370b that are used for transfer pipet 30, pond intubate 400 and transmission intubate 470 are linear-type, and correspondingly are provided with the operating position that is associated.In addition, pond arm 390b and transferring arm 460b can go up in two dimensions (not considering vertical direction above-mentioned) and move, and one of them arm of may command or two arms are positioned in the selected well of static sample tray 450 with the intubate that will be associated thus.Fig. 3 b has shown an embodiment of similar to Fig. 3 a linear ITC system, wherein the titrant delivery unit has been omitted, and transfer pipet shift unit 310c is arranged to transfer pipet 30 is placed in the correct position, is used for directly filling from the selected well of sample tray 450.In addition, fill port linkage unit 490 is provided with near the transfer pipet on the transfer pipet arm 380c 30, so that all can be connected on the fill port 500 when transfer pipet 30 is placed in cleaning station 320 and the filling position in the well of sample tray 450.
As mentioned above such, refuse fluidic system 360 is connected on the outlet port 350 that cleans station 320 to be used for regaining fluid from the cleaning station.According to an embodiment, refuse fluidic system 360 comprises the waste pump 510 that is used for optionally regaining from cleaning station 320 fluid, and it combines with one or more controllable valves 520 alternatively in order to guiding waste liquid stream.In other embodiments, waste pump can be the common pump that is used for ITC system 300 one or more fluidic systems, and one or more valve can be controlled the stream in this system respectively.Waste pump 510 can be to remove any suitable pump of the fluid in the cleaning station, for example peristaltic pump, syringe pump or the like.Fig. 4 a has shown the synoptic diagram of an embodiment of refuse fluidic system 360, the refuse operation valve 520 that it comprises the waste pump 510 (for example syringe pump) of reservoir type and is used to make waste pump and outlet port 350, Waste outlet 530 and escape hole 540 optionally to be connected/to disconnect.
As above mentioned and Fig. 4 a in Fig. 5 c more detailed demonstration like that, the syringe 200 of transfer pipet can comprise the fill port 500 that is positioned at its office, top, contacts thereby provide with the fluid of syringe cavity on plunger 230 is positioned in described fill port 500 time.In addition, ITC system 300 can comprise the fill port linkage unit 490 that matches, it is arranged to optionally be connected on the fill port 500, thereby between syringe cavity and injecting type fluidic system 480, provide the fluid contact, injecting type fluidic system 480 is arranged to optionally spur or promote liquid or gas passes syringe as part cleaning and padding, and this will carry out open in more detail hereinafter.As schematically disclosed, fill port 500 can be the hole of passing the wall of syringe 200, and this hole can be any suitable shape, and is for example straight or conical.Linkage unit 490 comprises that shape matches and/or has the link 550 of resilient material, thereby realizes the connection of reliable and fluid-tight.Injecting type fluidic system 480 also can be connected and transmit on the intubate 470, and is arranged to control during the clean operation of titrant transfer operation and transmission intubate 470 suction and the distribution of fluid.
According to an embodiment, injecting type fluidic system 480 comprises filling pump 560, so that optionally move or promote the liquid in the fluidic system to, it combines with one or more controllable valves 570,580,590 alternatively, in order to guiding fluid stream and purge gas source 600.In other embodiments, filling pump can be the common pump that is used for one or more fluidic systems of ITC system 300, and one or more valve can be distinguished the stream in the control system.Waste pump 560 can be any suitable pump that can promote or spur the liquid in the injecting type fluidic system, for example peristaltic pump, syringe pump or the like.Fig. 4 a has shown the synoptic diagram of an embodiment of injecting type fluidic system, and it comprises filling pump 560 (for example syringe pump), syringe operation valve 570, the syringe purge valve 580 of reservoir type and transmits intubate purge valve 590.Syringe operation valve 570 provide filling pump 560 fill port 500 to syringe 200, to transmit intubate 470, to a plurality of reagent reservoir 610a-d, disconnect to Waste outlet 620 and to the optionally connection of discharging port 630.Reagent reservoir 610a-d can comprise cleaning solution, to be used for clean injectors 210 and/or to transmit intubate 470 or the like.Fig. 4 b has shown the synoptic diagram of another embodiment of injecting type fluidic system 480 and refuse fluidic system 360, wherein, transmitting intubate 470 is not connected on the injecting type fluidic system 480, but be connected on the refuse fluidic system 360, the outlet port 350 via refuse fluidic system and cleaning station is sent to the titrant sample on the cleaning station 320 from transmitting intubate 470 thus.In addition, Fig. 4 a and 4b show that schematically transfer pipet assembly 30 is in the position that is used for titration, and wherein titration pin 210 is inserted in the sample cell 50.
In certain embodiments, as discussing before like that, syringe 200 is rotatable with respect to aupette 30, and is stirred motor 250 drivings and rotates.So in order to locate the position of fill port 500, fill port linkage unit 490 can comprise port aligning guide 640, it is punctual with 500 pairs of fill ports that it is arranged to when the link 550 of linkage unit, can prevent that syringe from rotating in predetermined angular position.Fig. 5 a has schematically shown an example of aligning guide 640 to Fig. 5 c, wherein, syringe 200 or any other parts (it is arranged to and can rotates about syringe 200) are provided with aligning parts 650, and fill port linkage unit 490 is provided with rotation stop element 660, it can be actuated in order to interfere the rotate path of aligning parts 650, and when aligning parts 650 was close to rotation stop element 660, link 550 was aimed at fill port 500 then.Alignment procedure comprises the following steps:
● actuate stop element 660 (Fig. 5 a),
● syringe is slowly rotated along predetermined direction, until preventing further rotation (Fig. 5 b) by the stop element 660 of being close to aligning parts 650, and
● actuate link 550, so that be connected to (Fig. 5 c) on the fill port 500.
Stop element 660 and link 550 can be that the electromagnetic drive type actuator of electronic device, solenoid etc. is actuated by the employing form, and perhaps they can be actuated by making hydraulic actuator that stop element 660 and link 550 move or pneumatic actuator or the like.In order to realize that between syringe fill port 500 and injecting type fluidic system 480 fluid-tight connects, available predetermined acting force is pressed against link 550 on the fill port 500.(not shown) in one embodiment, link 550 is actuated by the electromagnetic drive type actuator, so that link 550 moves and contacts with fill port, and link 550 is spring loaded about actuator, so sealing force is determined by the spring constant and the compression of described spring.
As disclosed among Fig. 2, fill port linkage unit 490 can be arranged on cleaning station 320 places, thereby allows the connection between syringe cavity and the injecting type fluidic system 480 when transfer pipet assembly 30 is arranged on cleaning station 320 places.But as disclosed among Fig. 3 b, fill port linkage unit 490 and the transfer pipet assembly 30 that is supported by transfer pipet shift unit 310 can be set together, can connect at the fluid that any operating position is set up between syringe fill port 500 and the injecting type fluidic system 480 thus.
According to an embodiment, ITC system 300 is set to, when the titration pin 210 of transfer pipet 30 is arranged in the cleaning cavity 340 of cleaning station 320, can utilize syringe fill port 500 by promoting one or more cleaning solutions and pass syringe 200 and titration pin 210 coming clean injectors 200 and titration pin 210 via syringe fill port 500.Afterwards system can by with gas via syringe fill port 500 blow pass syringe 200 and titration pin 210 and after cleaning dry injection device 200, pin 210 and cleaning station 320.
Under many situations, the syringe 200 with titrant filling transfer pipet assembly 30 in syringe 200 is important without any entrapped air simultaneously.In one embodiment, this realizes by from titrant source (for example inserting the cleaning station 320 of titration pin 210) titrant of predetermined being introduced the syringe, wherein, this predetermined is selected as greater than the syringe volume, and syringe is filled and titrant begins to leave syringe by fill port 500 thus.Line driver 220 is energized so that close fill port 500 under the fill port 500 by plunger 230 is moved to then.
Fig. 6 has schematically shown the example of the pond fluidic system 410 that is connected on the pond intubate 400, and it is used for distributing and regains sample cell 50 and also may be at the liquid in the reference pond 40.As discussing before, pond intubate 400 can be arranged to be positioned in the sample cell 50, in the well of sample tray 450, in the sample reservoir 430a-c of one or more big volumes and at sample and prepare in the station 420.According to an embodiment, pond fluidic system 410 comprises pond pump 670, and it is used for optionally distributing and regaining fluid by pond intubate 400, and it combines with one or more controllable valves 680,690 alternatively with stream of guiding pond cleaning fluid or the like.In other embodiments, pond pump 670 can be the common pump that is used for one or more fluidic systems 360,380,410 in the ITC system 300, and one or more valve can be distinguished the stream in the control system.Pond pump 670 can be any suitable pump that can distribute and regain the fluid in the sample cell 50, for example peristaltic pump, syringe pump or the like.Fig. 6 has shown the synoptic diagram of an embodiment of pond fluidic system 410, it comprises: the pond pump 670 of reservoir type (for example syringe pump), be used for optionally waste pump and intubate 400, four pond cleaning solution reservoir 700a-c, Waste outlets 710 and discharge the pond prepare control valve 680 that port 720 is connected disconnection, and purify selector valve 690, purify selector valve 690 and be used for intubate 400 is connected on pond preparation valve 680 or the purge gas source 600 to be used for dry intubate 400.
Fig. 7 has schematically shown the ITC system of Fig. 2, and wherein the operating position for each shift arm is shown by dotted line.
Fig. 8 a has schematically shown the example of state to Fig. 8 D, and wherein, the operation that is used for preparing transfer pipet and sample cell can be in the ITC of Fig. 2 system executed in parallel.
In Fig. 8 a, transfer pipet assembly 30 is placed in cleaning position, and the pin of titration simultaneously 210 is in cleaning station 320, to be used for the syringe clean cycle.During clean cycle, the link 550 of fill port linkage unit 490 is connected on the fill port 500 of syringe 200, and injecting type fluidic system 480 is arranged to promote and to spur one or more cleaning solutions and is passed syringe 200, alternatively gas (for example nitrogen) is blowed subsequently and passes syringe with dry injection device 200.Pass syringe in order to promote cleaning solution, at first syringe operation valve 570 is arranged on position A so that filling pump is connected on the suitable reagent reservoir 610a-d, and actuate filling pump 560 so that cleaning solution is drawn in its pump reservoir, then syringe operation valve 570 is arranged on position B so that filling pump 560 is connected on the fill port 500 of syringe 200, and actuate filling pump 560 and pass syringe 200, thus cleaning solution is assigned to the cleaning station 320 from titration pin 210 to promote cleaning solution.Complete syringe clean cycle can comprise twice or repeatedly promote identical or different cleaning solution (syringe valve position C-E) passes syringe 200, and may comprise that drawing liquid passes syringe 200 and enters in the pump reservoir from cleaning station 320, can more than once syringe 200 be passed in its promotion thus, perhaps discharge by the Waste outlet 620 of injecting type fluidic system 480.When filling pump 570 is arranged to promote continuously two or more different cleaning solutions and is passed syringe 200, by with cleaning fluid (for example water) filling pump reservoir filling pump 570 capable of washing, to avoid the pollution between the cleaning solution.By waste valves 520 is located at position A, optionally the liquid that will be assigned in the cleaning station 320 by waste pump 510 is recovered in the pump reservoir by outlet port 350, and can pass through Waste outlet 530 discharges by waste valves 520 being located at position B afterwards.
In Fig. 8 a, though the syringe clean cycle is carried out at cleaning station 320 places, titrant delivery unit 370 is arranged to by syringe valve 570 being located at position F and being utilized filling pump 560 drawing titrant and draw the titrant sample in the well from sample tray 450 from well.Drawing the operation of titrant from well can carry out when for example utilizing dry gas to purify syringe 200, but it is to carry out after cleaning and clean filling pump 560 and syringe valve 570 fully, to avoid pollution, in clean cycle, do not relate to filling pump 560 and syringe valve 570 thus.
In Fig. 8 a, also when the syringe clean cycle was carried out at cleaning station 320 places, pond preparatory unit 330 was set to remove sample before and clean sample cell 50 from sample cell 50.When sample cell 50 removes transfer pipet assembly 30, pond intubate 400 can be inserted in the sample cell 50, and by pond prepare control valve 680 is arranged on position A, can trigger pond pump 670 sample before is recovered in the pump reservoir, can sample before be discharged by Waste outlet 710 by pond prepare control valve 680 being located at position B afterwards.To carry out by one or more pond cleaning solutions that distribute and regain in the sample cell 50 after the cleaning of pond, pass through pond intubate blow gas (for example nitrogen) subsequently alternatively with dry sample pond 50.For cleaning solution is assigned in the sample cell, at first pond prepare control valve 680 is arranged on position C, D, E or F, so that pond pump 670 is connected on the suitable cleaning solution reservoir 700a-d, and actuate pond pump 670 cleaning solution is drawn in its pump reservoir, then pond prepare control valve 680 is arranged on position A so that pond pump 670 is connected on the intubate 400, and actuates pond pump 670 cleaning solution is assigned in the sample cell 50 by pond intubate 200.Regain and discharge cleaning solution by the waste port 710 of pond prepare control valve 680 afterwards.According to disclosed embodiment, during the cleaning course of pond, pond intubate 400 is retained in the sample cell, thereby make pond intubate 400 and pond 50 be cleaned simultaneously and prepare fresh sample liquids is sent to sample cell 50.
In Fig. 8 b, transfer pipet assembly 30 is placed on the place, centre position between sample cell 50 and the cleaning station 320, so that allow that the titrant of titrant delivery unit 370 transmits intubate 470 and arrives cleaning station 320, in order to distribute new titrant sample there, and the pond intubate 400 of allowing pond preparatory unit 300 arrives sample cells 50, in order in next step with fresh sample filling sample pond.Titrant delivery unit 370 is arranged to can be by being located at syringe valve 570 position F and utilizing filling pump 560 to distribute titrant and the titrant sample is assigned to the cleaning station from intubate 470.
In Fig. 8 b, the pond preparatory unit is arranged to draw fresh sample from the well of sample tray 450, by: intubate 400 insertions in pond are comprised in the selected well of required fresh sample, pond prepare control valve 680 is located at position A, and fresh sample is incorporated into the pump reservoir of pond pump 670 from this well.Alternatively, pond intubate 400 can be inserted among one of them sample reservoir 430a-c.
In Fig. 8 c, transfer pipet assembly 30 also is placed in cleaning position, and the pin of titration simultaneously 210 is in cleaning station 320, to use titrant filled syringe 200.As reference Fig. 5 a-c discusses in detail, during filled syringe 200, the link 550 of fill port linkage unit 490 is connected on the fill port 500 of syringe 200, and injecting type fluidic system 480 is set to by titration pin 210 titrant be introduced in the syringe 200, through fill port 500, plunger 230 is reduced to close fill port 500 until smaller volume.By by this way titrant being drawn in the syringe, avoided the air that dams in the titrant effectively.In Fig. 8 b during the disclosed state, titrant delivery unit 370 is inactive basically, but pond preparatory unit 330 is positioned to make pond intubate 400 in sample cell 50, with with the fresh sample filling sample pond of exact magnitude, this is by being arranged at position A with pond prepare control valve 680 and triggering pond pump 670 and will be included in fresh sample in the pump reservoir and be assigned in the sample cell 50 and realize.
In Fig. 8 a, transfer pipet assembly 30 is placed in the titration position, and wherein titration pin 210 is tested to carry out ITC in sample cell 50.Titrant delivery unit 370 is positioned to make the titrant intubate now in cleaning station 320, to carry out cleaning it before next titrant transfer operation.This clean cycle can be used for the basic identical of syringe 200.During the disclosed state, pond preparatory unit 330 is inactive basically in Fig. 8 b, and demonstration makes pond intubate 400 prepare in the station 420 at sample.
The example of liquid handling order comprises:
The pond cleaning:
A. pond intubate 400 is inserted in the pond 40,50 that is shelved on the bottom.
B. by pond intubate 400 the pond content is drawn in the pond pump 680, and is assigned to waste port 710.
C. from cleaning solution reservoir 700a-d, water is drawn in the pump reservoir of pond pump 680, and is assigned to waste port 710 to clean syringe.
D. from one of them of cleaning solution reservoir 700a-d cleaning solution is drawn to the pump reservoir of pond pump 680, and the pond is filled required accurate amount it is assigned in the pond 40,50 by pond intubate 400,
E. cleaning solution is from pump reservoir 40,50 circulations back and forth to the pond of pond pump 680, so that cleaning pond 40,50.
F. make these steps that start from step b repeat predetermined times until pond 40,50.
G. the pond is evacuated to refuse as among the step b.
H. pond intubate 400 moves on the sample preparation station 420, and is dried by blow gas (for example nitrogen).If in the loading process of pond, comprise the degassing, before drying, should clean sample so and prepare station 420.
The transfer pipet cleaning:
A. transfer pipet 30 is placed cleaning/filling station 320, and connect fill port 500.
Transfer pipet plunger 230 is elevated on the fill port 500, crosses the syringe 200 of transfer pipet 30 to allow flow of liquid.
C. at first be that air is assigned to the fill port 500 from syringe pump 560 then with water,
Enter in cleaning/filling station 320 by syringe 200 and titration pin 210.Simultaneously, by Waste outlet 350 bottom of this water from cleaning/filling station 320 is drawn to the waste pump 510 in a large number.
D. waste pump 510 stops, and passes through the water that transfer pipet 30 distributes exact magnitudes, so that will clean/fill the top that station 320 is filled to the outside of titration pin 210.Water circulates back and forth, so that at whole syringe 200 of inside and outside cleaning and titration pin.
E. repeating step c.
F. use methyl alcohol repeating step d.
G. repeating step c.
H. blow nitrogen with dry this system by fill port 500.
I. remove transfer pipet 30 from cleaning/filling station 320, come load station 320 to allow titrant delivery unit 370 usefulness titrant samples.
J. water cleans syringe pump 560, to remove any methyl alcohol from this system.
Load in the pond:
A. the titrant sample is drawn to the pond intubate 400 from sample tray 450 or sample reservoir 430a-c.Then it is assigned in the pond lentamente to prevent bubble.Alternatively, sample is assigned to sample prepares in the station 420, so that it is heated before in being sent to pond 50 and mixes (degassing).
Transfer pipet loads:
A. titrant is drawn to titrant from sample tray 450 and transmits the intubate 470, and be assigned in cleaning/filling station 320.
B. transfer pipet 30 is placed in cleaning/filling station 320 and connects fill port 500.
Plunger 230 is elevated on the fill port 500 to allow that flow of liquid crosses transfer pipet.
D. by syringe pump 560 titrant of precise volumes is drawn to titration pin 210, made a small amount of titrant leave fill port 500 thereby be full of syringe 200 excessively.
E. plunger 230 is lowered under the fill port 500, and remaining titration pin 210 and transfer pipet syringe 200 are filled up fully.
Titrant transmits cleaning:
A. titrant transmitted intubate 470 and be placed in cleaning/filling station 320, and water cleans, afterwards under the mode identical with the syringe 200 of cleaning and dry transfer pipet with methyl alcohol with its cleaning and drying.
Should be appreciated that any feature of describing about arbitrary embodiment can use separately, perhaps be used in combination, and can be used in combination with one or more features of any other embodiment or any combination of any other embodiment with described further feature.In addition, under the situation that does not break away from the scope of the present invention defined in the claims, there not be the equivalent and the modification of description above also can using.

Claims (17)

1. hot (ITC) system of automatic isothermal titration trace comprises:
Microcalorimeter, described microcalorimeter have sample cell and with reference to the pond, and described sample cell can arrive via the sample cell post, and describedly can arrive via reference pond post with reference to the pond;
The aupette assembly, described aupette assembly comprises the syringe of band titration pin, described titration pin is set in order to insert in the described sample cell to be used to supply with titrant, and described transfer pipet assembly comprises that driver is to be used for driving the plunger of described syringe;
The transfer pipet shift unit, described transfer pipet shift unit is supporting described transfer pipet assembly, and is set in order to transfer pipet is placed on the position that is used for titration, cleaning and padding;
The cleaning station that is used for described titration pin; And
Pond preparatory unit, described pond preparatory unit are set to when described transfer pipet is placed on the another location different with the position that is used for titration, and executable operations is to be used for changing the sample liquids of described sample cell.
2. automatic ITC according to claim 1 system, it is characterized in that, described cleaning station comprises the cleaning cavity, described cleaning cavity is set to when described transfer pipet assembly is placed on the position that is used to clean, at least hold described titration pin and during titration, immerse part in the described sample, wherein, described cleaning station comprises the bottom that is positioned at described cleaning cavity and is connected Waste outlet port on the refuse fluidic system.
3. automatic ITC according to claim 2 system is characterized in that described refuse fluidic system comprises that waste pump is to be used for optionally regaining fluid from described cleaning station.
4. automatic ITC according to claim 1 system is characterized in that,
Described syringe comprises the fill port that is positioned at its top, provides in the time of on described plunger is positioned described fill port with the fluid of described syringe cavity to contact, and
Described automatic ITC system comprises the fill port linkage unit, described fill port linkage unit is set to optionally to be connected on the described fill port, thereby between described syringe cavity and injecting type fluidic system, provide the fluid contact, so that optionally pulling or promotion liquid or gas pass described syringe.
5. automatic ITC according to claim 4 system, it is characterized in that, described syringe can and be stirred motor driven and rotates with respect to the rotation of described aupette, described fill port linkage unit comprises the port aligning guide, and described port aligning guide is set to rotate at the predetermined angular position place preventing described syringe on time at link and described fill port.
6. automatic ITC according to claim 4 system, it is characterized in that, described fill port linkage unit is arranged on described cleaning station place, allows the connection between described syringe cavity and the described injecting type fluidic system when being arranged on described cleaning station place with the described transfer pipet of box lunch.
7. automatic ITC according to claim 4 system is characterized in that described injecting type fluidic system comprises syringe filling-valve device, described syringe filling-valve device can:
The described fill port of described syringe is connected on the purge gas source, and be connected on the syringe filling pump and
Described syringe filling pump is connected on one or more cleaning solution reservoirs, and is connected on the Waste outlet.
8. automatic ITC according to claim 7 system, it is characterized in that, described injecting type fluidic system is set to, when the described titration pin of described transfer pipet is arranged in the described cleaning cavity, can one or more cleaning solutions pass described syringe via described syringe fill port and described titration pin cleans described syringe and described titration pin by promoting.
9. automatic ITC according to claim 8 system, it is characterized in that, described injecting type fluidic system is set to, and after cleaning described syringe and described titration pin, via described syringe fill port gas is blowed and to pass described syringe and described titration pin.
10. automatic ITC according to claim 4 system, it is characterized in that, described injecting type fluidic system is set to, by being introduced from the titrant source of wherein having inserted described titration pin, the titrant of predetermined utilize titrant to fill described syringe the described syringe, wherein, described predetermined is selected as bigger than the volume of described syringe, be full of described syringe so that cross, and line driver is set in order to subsequently described plunger is positioned under the described fill port, so that close described fill port.
11. automatic ITC according to claim 10 system it is characterized in that described titrant source is the well in the sample tray, and wherein, described transfer pipet shift unit is set in order to described transfer pipet is placed on the position that is used for from described well filling sample.
12. automatic ITC according to claim 10 system, it is characterized in that, described automatic ITC system comprises the titrant delivery unit, described titrant delivery unit is set in order to titrant is sent to form from the first titrant source for filling the second titrant source of station, and, wherein, described transfer pipet shift unit is set to be used for the position of filling at described filling station place in order to described transfer pipet is placed on.
13. automatic ITC according to claim 12 system is characterized in that the described first titrant source is the well in the sample tray.
14. automatic ITC according to claim 12 system, it is characterized in that, described titrant delivery unit comprises and being set in order to drawing the intubate of titrant from the described first titrant source, and is connected on the port in the described filling station to be used for the titrant of described volume is sent to from described intubate the fluidic system of described filling station.
15. automatic ITC according to claim 12 system, it is characterized in that, described titrant delivery unit comprises intubate, described intubate is set in order to draw titrant from the described first titrant source, and be configured such that described intubate moves to described filling station, so that distribute described titrant there.
16. automatic ITC according to claim 12 system is characterized in that described filling station and described cleaning station are combined into a kind of station of combination.
17. automatic ITC according to claim 1 system is characterized in that described pond preparatory unit comprises intubate, described intubate can move so that be inserted in the described sample cell.
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